1. Field of the Invention
This invention relates to a apparatus for display of a processed, condensed derivative of electroencephalographic (EEG) signals.
2. Discussion of the Related Art
Cerebral/neural injuries in pre-term infants are telatively difficult to assess and to track during their course, using skills and equipment available at the time of this application; yet intervention may be highly desirable. Magnetic resonance imaging (MRI) is the only reliable non-invasive assessment available to a neo-natal intensive care unit. MRI is limited to (a) revealing lesions in older infants, typically over 34 weeks, and (b) to showing structural correlates of changes that are already too late for intervention, it being 3-4 days before MRI scans show injury. Ultrasound imaging is significantly less reliable than MRI in this area. It has been estimated that up to 70% of cases of apparent hypoxic-ischemic injury are missed.
Very premature infants have a markedly increased risk of neurological morbidity [Volpe, Prev. Med., 23:638-645, 1994]. A recent study using cranial ultrasonography revealed that only 2% of infants born at 23 weeks, 21% at 24 weeks and 69% at 25 weeks survived without severe abnormalities [Allen et al., New Eng. J. Med., 329:1597-1601, 1993]. White matter brain damage is a characteristic of these injuries. Patterns of damage range from subtle gliosis (telencephalic leukomalacia) through to severe cystic infarctions of the periventricular and subcortical white matter [Volpe, op. cit.].
Histopathologic studies indicate some of these lesions develop prenatally, others postnatally. Poor neurological outcome is associated with the presence of these white matter injuries [Guit et al., Radiolog, 175:107-109, 1990]. Severe periventricular lesions are strongly associated with cerebral palsy [Hoon, J. Perinatol., 15:389-394, 1995].
Long term neurological outcome appears to be similarly compromised. In a group of less than 32 week old premature infants reviewed at the age of 9 years 19% were in special education, 32% were in a grade below the appropriate level for their age and 38% required special assistance [Hille et al., J Pediatr., 125:426-434, 1994]. Similarly, another study has shown that in very premature infants about 5-15% develop major spastic motor deficits and an additional 25-50% exhibit developmental and cognitive disabilities [Volpe, Biol. Neonate, 62:231-242, 1992]. The etiology of these lesions is not completely understood [Armstrong, Semin. Perinatol., 17:342-350, 1993], but they are thought to occur secondary to various prenatal environmental and genetic factors [Lou, Brain Dev., 16:423-431, 1994].
Cerebral hypoperfusion is considered to be a significant final common pathway in the pathogenesis of these encephalopathies [Lou, op. cit.]. Experimental and epidemiological studies generally support this hypothesis. For example, intrapartum acidosis and asphyxia in the premature infant carry a high risk of periventricular leukomalacia [Low et al., Am. J. Obstet. Gynecol, 162:977-981, 1990]. Also, both increased levels of hypoxanthine and prolonged metabolic acidosis in the neonatal period are associated with a high risk of periventricular lesions [Russel et al., Arch. Dis. Child., 67:388-392, 1992; Low et al., op. cit.]. In particular, periventricular lesions are probably caused by cerebral hypoxia-ischemia following arterial hypotension [Iida et al., Pediatr. Neurol., 8:205-209, 1992]. Cerebral hypoxia-ischemia may arise from problems associated with prematurity including respiratory distress syndrome, patent ductus arteriosis, necrotizing enterocolitis and sepsis. There is considerable variation in the pattern of lesions observed and a range of factors are likely to influence outcome, including gestational age and the severity and nature of the insult [Gluckman et al., “Proceedings of the Alfred Benzon Symposium No. 37, Munksgaard, Copenhagen, 1993. ]Other factors such as hypoglycemia, infections or toxemia are also likely to be important [Piekkala et al:, Early Hum. Dev., 13:249-268, 1986].
Current methods for assessing brain injury reveal damaged areas of the brain, but do not identify those premature infants at risk of suffering a neural injury. Brain damage assessed by neurological examination is of limited prognostic value, especially for those pre-term infants on life support. Ultrasonography is also used and reveals lesions as white matter echodensities and echolucencies, which are useful in predicting future handicap, such as cerebral palsy. However, this approach is less suitable for monitoring and detecting pathophysiologic events which may occur over several days, the knowledge of which could be used to minimize or avoid further injury. Greater reliance needs to be placed on other investigations such as pathophysiologic measures [Hill, Clin. Invest. Med., 16:141-148, 1993]. Doppler cerebral hemodynamic measures have not been proven to be predictive of outcome [Shortland et al., J. Perinat. Med., 18:411-417, 1990]. In the more mature brain the EEG signal can be used to predict severe loss of the superficial neurons that generate this signal [Williams et al., Ann. Neurol., 31:14-21,1992].
Two patterns of white matter damage can occur: “subtle” white-matter damage which manifests as gliosis, impaired myelination, and ventriculomegaly, and is often termed telencephalic leukomalacia; and “severe” cystic infarctions within the periventricular and subcortical white matter. The former lesions are associated with cognitive deficits and the latter are strongly associated with cerebral palsy.
Histopathological studies indicate the timing of injury is variable—some injuries may develop prenatally whereas many others appear to develop during the first postnatal weeks. However in surviving infants the timing of injuries is typically unclear and there are considerable problems with detecting when these white matter injuries occur [Murphy et al., Arch. Dis. Child Fetal Neonat. Ed., 75(1 Special Issue SI):F 27-F32, 1996]. The inability to detect the onset of injury makes management difficult. For example, if a subtle or severe injury to the deep white matter could be rapidly detected, then the injurious factor could be corrected or treatment applied. The use of EEG-related parameters is believed to closely reflect the development of subtle or severe injury and consequent brain lesions within white matter (tracts) and/or gray matter (neuron bodies).
The appearance of positive Rolandic sharp waves (PRSW) in an EEG has been found to be specific for some cases, but to give false negative results in as many as 70% of extremely low birth weight infants even if it is done by a person experienced in interpreting EEG traces. One problem to be solved is to provide a more sensitive test than one relying on the PRSW, so that at least some types of brain injury can be recognized, their severity and coverage may be quantified and their effects may be alleviated by timely intervention. Many such lesions (though not all, given the brain's ability to compensate) will manifest themselves as adverse outcomes by about 18 months of age and an ability to predict such outcomes is desired.
It is evident from the above that there is a need for a device capable of reporting accurately on the current level of a pre-term infant's neural status; to be useful in prediction of outcomes and to lead to a considerable improvement in the treatment of infants with, or likely to develop, white matter neural injury. The inventor's group is already active in this area (see, for example, WO 00/13650). After working with a fetal sheep model, the inventor has constructed a Brain Rescue Monitor (see, for example, U.S. Pat. No. 5,807,270 and WO 98/57139), using EEG-type skin electrodes to collect signals for processing in the frequency domain, and to make real-time displays of trends of neural status occurring over periods of time from minutes to weeks.
Related to long-term EEG-based recordings, a further problem remaining to be solved is to reliably and consistently recover, over an extended period of perhaps 6 hours to a week, and in a non-ideal space, the very weak signal that comprises a typical EEG. This signal is easily corrupted by intrinsic noise and external interference. The BRM is suitable for long-term, semi-automatic monitoring of neural function although the lack of direct, continuous human supervision over signal quality imposes a particular requirement for effective rejection of artifacts inadvertently included with the data. At the same time, a real pathophysiological change, likely to influence treatment, must not be altered by any filtering procedure.